Hypogonadotropic hypogonadism (HH) is characterized by deficiency in the production of the gonadotropins. LH and FSH. and can be a reversible form of infertility. Causes of HH include deficient production or regulation of hypothalamic GnRH as well as abnormal responsiveness of the pituitary gonadotrope cell. Remarkably, studies of pathways that regulate expression of the gonadotropin genes are now pointing the way towards disorders that underlie reproductive dysfunction. Transcription factors such as SF-1 and DAX-1 appear to play a key role in the development of the normal gonadotrope phenotype. Mutations in DAX-1 have been shown to cause X-linked adrenal hypoplasia congenita (AHC) and associated HH. A gene knockout of SF-1 results in a phenotypically similar disorder in a mouse model. In both cases, there is evidence for abnormalities in GnRH production and gonadotrope responsiveness. Preliminary studies suggest that these transcription factors regulate the expression of an array of gonadotrope-specific genes including the GnRH receptor and the alpha and beta-subunit genes for LH and FSH. The goal of this project is to perform an integrated series of studies that define the effects of DAX-1 and SF-1 mutations at a clinical level. in animal models, and in terms of how these proteins function at a cellular level. The specific aims are to: 1) Identify DAX-1 and SF-1 gene mutations as causes of hypogonadotropic hypogonadism in humans and to characterize the clinical phenotypes using detailed studies of the hypothalamic-pituitary-gonadal axis. 2) Examine the developmental and functional relationships of SF-1 and DAX-1 in the pituitary and hypothalamus. The spaciotemporal patterns of SF-1 and DAX-1 expression will be determined and a DAX-1 knockout mouse model will be created to evaluate the functional and developmental role of this transcription factor in an animal model. 3) Identify and characterize the DNA-binding and functional properties of SF-1 and DAX-1 with respect to target genes expressed in gonadotrope cells. These studies will provide new insights into the genetic and cellular basis of gonadotropin deficiency syndromes and will provide a platform for rational therapeutic interventions.